An Oxygen Walk Approach for C3 Selective Hydroxylation of Pyridines

Abstract

Selective C3 functionalization of unbiased pyridines represents a significant challenge in organic synthesis. While seminal work in this area has enabled access to various C3-substituted pyridines via dearomatized intermediates, the direct introduction of a hydroxy group at this position is still challenging. In this context, we have developed a valence isomerization reaction triggered by photoexcitation of pyridine N-oxides to deliver synthetically challenging C3-hydroxy pyridine products.

1 Introduction

2 Recent Advances in Radical-Based Pyridine Functionalization via Pyridine N-Oxides

3 C3-Selective Hydroxylation of Pyridines through Oxygen Walking

4 Conclusion

Key words

pyridine N-oxides - hydroxylation - oxygen walk - photorearrangement - late-stage functionalization

Publication History

Received: 02 January 2025

Accepted after revision: 30 January 2025

Article published online:
14 March 2025

• References


For selected reviews and examples, see:
• 1a Bhutani P, Joshi G, Raja N, Bachhav N, Rajanna PK, Bhutani H, Paul AT, Kumar R. J. Med. Chem. 2021; 64: 2339
• 1b Kallitsis JK, Geormezi M, Neophytides SG. Polym. Int. 2009; 58: 1226
• 1c Zafar MN, Atif AH, Nazar MF, Sumrra SH, Gul-E- Saba, Paracha R. Russ. J. Coord. Chem. 2016; 42: 1

For selected reviews and examples, see:
• 2a Josephitis CM, Nguyen HM. H, McNally A. Chem. Rev. 2023; 123: 7655
• 2b Failla M, Lombardo GW, Orlando P, Fiorito D, Bombonato E, Ronchi P, Passarella D, Fasano V. Eur. J. Org. Chem. 2023; 26: e202300074
• 3 Cao H, Cheng Q, Studer A. Angew. Chem. Int. Ed. 2023; 62: e202302941

For selected reviews and examples, see:
• 4a Wright JS, Scott PJ. H, Steel PG. Angew. Chem. Int. Ed. 2021; 60: 2796
• 4b Larsen MA, Hartwig JF. J. Am. Chem. Soc. 2014; 136: 4287
• 4c Yang L, Uemura N, Nakao Y. J. Am. Chem. Soc. 2019; 141: 7972

For selected examples, see:
• 5a Boyle BT, Levy JN, de Lescure L, Paton RS, McNally A. Science 2022; 378: 773
• 5b Cao H, Cheng Q, Studer A. Science 2022; 378: 779
• 5c Muta R, Torigoe T, Kuninobu Y. Org. Lett. 2022; 24: 8218
• 5d Tian J.-J, Li R.-R, Tian G.-X, Wang X.-C. Angew. Chem. Int. Ed. 2023; 62: e202307697

For selected reviews and examples, see:
• 6a Proctor RS. J, Phipps RJ. Angew. Chem. Int. Ed. 2019; 58: 13666
• 6b Satheesh V, Deng Y. J. Org. Chem. 2024; 89: 11864
• 6c Ang HT, Miao Y, Ravelli D, Wu J. Nat. Synth. 2024; 3: 568
• 6d Habib I, Singha K, Hossain M. ChemistrySelect 2023; 8: e202204099
• 6e Oudeyer S, Levacher V, Beucher H, Brière J.-F. Molecules 2023; 28: 1071
• 7 Cai C.-Y, Chen S.-J, Merchant RR, Kanda Y, Qin T. J. Am. Chem. Soc. 2024; 146: 24257

For selected reviews and examples, see:
• 8a Kutasevich AV, Perevalov VP, Mityanov VS. Eur. J. Org. Chem. 2021; 2021: 357
• 8b Petrosyan A, Hauptmann R, Pospech J. Eur. J. Org. Chem. 2018; 2018: 5237
• 8c Wang Y, Zhang L. Synthesis 2015; 47: 289
• 9 Kobus M, Friedrich T, Zorn E, Burmeister N, Maison W. J. Med. Chem. 2024; 67: 5168
• 10 Li G, Yang S, Lv B, Han Q, Ma X, Sun K, Wang Z, Zhao F, Lv Y, Wu H. Org. Biomol. Chem. 2015; 13: 11184
• 11 Duncton MA. J. Med. Chem. Commun. 2011; 2: 1135
• 12 Lantaño B, Barata-Vallejo S, Postigo A. Org. Biomol. Chem. 2018; 16: 6718
• 13 Lo JC, Kim D, Pan C.-M, Edwards JT, Yabe Y, Gui J, Qin T, Gutiérrez S, Giacoboni J, Smith MW, Holland PL, Baran PS. J. Am. Chem. Soc. 2017; 139: 2484
• 14 Sun AC, McClain EJ, Beatty JW, Stephenson CR. J. Org. Lett. 2018; 20: 3487
• 15 Xu J.-H, Wu W.-B, Wu J. Org. Lett. 2019; 21: 5321
• 16 Schlegel M, Qian S, Nicewicz DA. ACS Catal. 2022; 12: 10499
• 17 Yue F, Li M, Yang K, Song H, Liu Y, Wang Q. Chem. Sci. 2024; 15: 14241

For selected reviews and examples, see:
• 18a Albini A, Alpegiani M. Chem. Rev. 1984; 84: 43
• 18b Poole JS. In Heterocyclic N-Oxides . Larionov OV. Springer; Cham: 2017: 111
• 19a Feng Z, Allred TK, Hurlow EE, Harran PG. J. Am. Chem. Soc. 2019; 141: 2274
• 19b Hurlow EE, Lin JB, Dweck MJ, Nuryyeva S, Feng Z, Allred TK, Houk KN, Harran PG. J. Am. Chem. Soc. 2020; 142: 20717

For selected reviews and examples, see:
• 20a Streith J, Danner B, Sigwalt C. Chem. Commun. (London) 1967; 979b
• 20b Basistyi VS, Frederich JH. Org. Lett. 2022; 24: 1907
• 21 Ascenzi-Pettenuzzo C, Nganda J, Deng Y. ChemCatChem 2023; 15: e202300953

For selected reviews and examples, see:
• 22a Liang J, Han Q, Tan Y, Ding H, Li J. Front. Mol. Biosci. 2019; 6: 4
• 22b Cramer J, Sager CP, Ernst B. J. Med. Chem. 2019; 62: 8915
• 23 Thirumalaikumar M. Org. Prep. Proced. Int. 2022; 54: 1
• 24 Woo J, Christian AH, Burgess SA, Jiang Y, Mansoor UF, Levin MD. Science 2022; 376: 527
• 25 Berson JA, Willcott III MR. J. Am. Chem. Soc. 1965; 87: 2751